tbuckley/cabot-search huggingface dataset:
Phase Ib study of avelumab and novel AXL inhibitor avb-S6-500 in patients with metastatic urothelial carcinoma (mUC).
Authors: Abhishek Tripathi, Melissa Clingerman, Riza Celine Fabreo, Adanma Ayanambakkam, Brian Cross, Kelly Lynn Stratton, Michael Cookson, Sumanta K. Pal, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2022)

4579 Background: AXL is a member of the mammalian Tyro3/AXL/Mer (TAM) receptor tyrosine kinase family, which upon binding to its ligand Gas6 promotes immunosuppression in the tumor microenvironment. AVB-S6-500 (AVB) is a novel AXL pathway inhibitor which binds to circulating Gas6 and inhibits ligand-dependent AXL signaling. In this phase Ib investigator-initiated trial (NCT04004442), we evaluated the safety, tolerability, pharmacodynamics, and preliminary antitumor efficacy of AVB with the anti-PD-L1 antibody avelumab in mUC. Methods: Patients with PD-1/L1 inhibitor naïve locally advanced unresectable or mUC with measurable disease were eligible if they were either in-eligible for, refractory to, or declined platinum-based chemotherapy. Employing a 3+3 dose escalation design, patients were treated with AVB 5mg/kg weekly (dose level; DL1), or 10 (DL2), 15 (DL3), or 20 (DL4) mg/kg every two weeks along with avelumab 800 mg every 2 weeks administered intravenously. The safety and tolerability of the combination as measured by the incidence of dose limiting toxicities (DLTs) was the primary endpoint while objective response rate (ORR) per RECIST 1.1 was key secondary endpoint. Pharmacodynamic studies evaluated baseline and on therapy (C2D1) Gas6 levels. Results: To date, a total of 15 patients have been enrolled (DL1: n = 3, DL2: n = 7, DL3: n = 3 and DL4: n = 2). Among the 13 evaluable patients, DLT was observed in 1 patient (grade 3 fatigue; DL2). Grade ≥3 adverse events irrespective of attribution were seen in 6 patients which included UTI (n = 3), hyponatremia (n = 1), elevated creatinine (n = 1), and anemia, thrombocytopenia, hematuria, anorexia and sepsis (n = 1 each; all in same patient). No treatment related deaths were noted. While enrollment on DL4 is ongoing, the maximum tolerated dose for AVB has not been reached. Treatment with AVB effectively suppressed circulating Gas6 levels from baseline (median: 28.4 ng/mL; range: 20.4-54.0 ng/mL) to below threshold of detection in 85% (n = 11/13) of patients. Median follow up was 10 months (95% CI: 3.9, 18.55). Confirmed ORR was 38% (n = 5/13) while 1 patient had stable disease as best response. Durable responses lasting &gt; 6 months were seen in 3 patients (7, 19 and 21 mos) who continue to be on treatment without disease progression. Additional correlative studies investigating AXL, Gas6, PD-L1 expression and gene expression signatures are currently underway. Conclusions: Concurrent avelumab and AVB was safe and AVB effectively neutralized circulating Gas6 across DLs. Albeit small sample size, the efficacy of the combination was encouraging and ORR compares favorably to that previously reported with PD-1/L1 inhibitor monotherapy. Updated safety, efficacy and biomarker data will be presented. Clinical trial information: NCT04004442.
Seeking racial equity in hematology and oncology: A fellow-led educational series to promote reflection and action.
Authors: Jacob Newton Stein, Jacquelyne Janean Gaddy, Jonathan D Sorah, Melissa Wooten, Keisha Gibson, Frances A. Collichio
Journal: Journal of Clinical Oncology (2022)

11004 Background: With the murder of George Floyd and health disparities laid bare by the COVID pandemic, the US is reckoning with racial injustice. Across medicine and oncology, institutions are grappling with how to address systemic racism and improve care for patients of color. At the University of North Carolina (UNC), trainees developed an educational curriculum to raise awareness of implicit bias and introduce methods to address racial inequities. We present our findings on feasibility and acceptability of a fellow-led course on racism in medicine at a major academic medical center. Methods: UNC oncology fellows adapted a curriculum on implicit bias and racism in medicine in spring 2021. Our aims were 1) to improve knowledge and awareness about implicit bias and systemic racism and 2) introduce methods to address racial inequities. We used lived experiences and collated materials from scientific literature and lay media to illustrate key points. Sessions were: 1) Introduction and Implicit Bias, 2) Implicit Bias in Action: A Case Study, 3) Race-Based Metrics: Journal Club, 4) Career Perspective on Equity in Oncology. Videos, journal articles, and group discussion were employed to appeal to many learning styles. Results: Four sessions were held virtually for the Divisions of Oncology and Hematology. Attendance ranged from 28 to 35 per session. A post curriculum survey assessed perception of racial inequality in medicine and the series’ effects using a Likert scale. Twenty-nine participants completed the survey, 12 of whom were fellows. Of all participants, 71% reported that the course improved knowledge or awareness of racial inequities "some" or "a great deal" and 61% reported that it improved their comfort level addressing racial inequities "some" or "a great deal." All participants endorsed at least “some” racial inequity in medicine. Notably, over 75% of participants indicated interest in further sessions. Conclusions: Formulation of an educational curriculum by fellows and delivered in a division wide setting was feasible and well received by participants with robust discussion and interest in further work. Fundamental to this series’ effectiveness was creating a space for discussion and reflection among colleagues. The goals of improving knowledge and introducing methods to address racial inequities were met. Importantly, our course was integrated alongside institutional efforts on DEI. We were limited by a lack of pre-course survey results due to a technical error. Given the current groundswell of interest and focus in improving racial equity in our society, we encourage other institutions to take similar steps to highlight issues of systemic racism and continue to move our field in the right direction.
Phase II randomized double blind trial of axitinib (Axi) +/- PF-04518600, an OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in metastatic renal cell carcinoma (mRCC).
Authors: Sarmad Sadeghi, Rahul Atul Parikh, Denice D. Tsao-Wei, Susan G. Groshen, Ming Li, Leonard Joseph Appleman, Scott T. Tagawa, David M. Nanus, Ana M. Molina, Cheryl Kefauver, Moshe Chaim Ornstein, Brian I. Rini, Robert Dreicer, David I. Quinn, Primo "Lucky" N. Lara
Journal: Journal of Clinical Oncology (2022)

4529 Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P &lt; 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]
A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2 overexpressing solid tumors.
Authors: Kim Anna Reiss, Yuan Yuan, Naoto T. Ueno, Melissa Lynne Johnson, Saar Gill, Elizabeth Claire Dees, Joseph Chao, Mathew Angelos, Olga Shestova, Jonathan Stuart Serody, Saul Priceman, Debora Barton, Ramona F. Swaby, Amy Ronczka, Thomas Condamine, Daniel Cushing, Rehman Qureshi, Madison Kremp, Michael Klichinsky, Yara Abdou
Journal: Journal of Clinical Oncology (2022)

TPS2677 Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but have had less success in those with solid tumors. Macrophages are actively recruited and abundantly present in the solid tumor microenvironment (sTME). Tumor associated macrophages are predominantly immunosuppressive and support tumor growth (M2), while a subset of proinflammatory macrophages enhance anti-tumor immunogenicity (M1). M1 macrophage function can be augmented by CAR expression to selectively recognize and phagocytose antigen overexpressing cancer cells. Moreover, CAR macrophages can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many solid tumors (Table). CT-0508 is a cell product comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pt) with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2. Pt previously treated with available therapies, including anti-HER2 therapies, as indicated, and subsequent progression are permitted. Filgrastim is used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 is manufactured, prepared, and cryopreserved from mobilized peripheral blood monocytes. Group 1 pt (n=9) receive CT-0508 infusion split over D1, 3, and 5. A Safety Review Committee will review dose limiting toxicities. Group 2 pt (n=9) will receive the full CT-0508 infusion on D1. Pre- and post-treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Radiographic imaging is also being conducted to assess preliminary tumor activity. Clinical trial information: NCT04660929. [Table: see text]
Facility type and it's impact on survival in Ewing's sarcoma: An NCDB analysis.
Authors: Marco Braaten, Jacob Braaten, Vincent Eaton
Journal: Journal of Clinical Oncology (2022)

e23505 Background: Previous studies have reported a significant association between facility type and survival in cancer patients. This study aimed to investigate the impact of treatment facility type on overall survival for Ewing’s Sarcoma. A secondary objective was to identify differences in distribution of demographic variables between facility types. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with Ewing’s sarcoma from 2004 to 2018. Four facility types were identified: Academic/Research Programs, Community Cancer Programs, Comprehensive Community Center Programs, and Integrated Network Cancer Programs. Descriptive statistics and Kaplan Meier curves were used to measure survival in these patients and Chi-square was used to evaluate differences in demographics. Data was analyzed using SPSS and statistical significance was set at α = 0.05. Results: Of 269 patients queried, 49% were treated at an academic facility. Academic Programs had the longest median survival of 54 months; Community Cancer Programs had the shortest median survival of 9 months. Statistically significant survival differences were found between all facility types on log-rank comparison (p &lt; 0.050), except for survival between Integrated Network and Community Cancer Programs (p = 0.162). Academic Programs had the highest overall survival when compared to Community Cancer Programs (p = 0.000), Comprehensive Community Cancer Programs (p = 0.026), and Integrated Cancer Networks p = (0.003). Chi-Square analysis revealed an association between facility type and cancer stage at diagnosis (p = 0.044) as well as between facility type and primary payer status (p = 0.026). Notably, 58% of patients treated at Community Programs presented with stage IV disease and 41% were insured by Medicare. Additional log-rank comparisons and Kaplan Meier curves showed private insurance was associated with significantly higher survival compared with Medicaid (p = 0.043), Medicare (p = 0.001) and uninsured patients (p = 0.010). Patients treated at Comprehensive Community (70%) and Academic Programs (67%) had the highest proportion of patients with private insurance. Conclusions: This study showed that Ewing Sarcoma patients treated in an Academic/Research program facility experienced increased survival compared with other facility types. Patients treated at Community Cancer Programs were more likely to present with stage IV disease and were more likely to be on Medicare. Future studies may investigate additional factors that influence potential barriers to care for Ewing Sarcoma patients.[Table: see text]
Tumor thrombosis in extremity soft tissue sarcomas.
Authors: Oksana V. Katelnitskaya, Evgeniya M. Nepomnyashchaya, Tatiana V. Ausheva, Artem A. Barashev, Larisa N. Vashchenko, Pavel V. Chernogorov, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e23551 Background: Malignant tumors of bones and soft tissues often reach large sizes, compress and invade the major vessels, leading to the development of venous thrombosis. Venous thrombosis is difficult to distinguish from tumor thrombosis in the preoperative period. However, the management differs. Both conditions require anticoagulant therapy, but tumor thrombosis requires expanding intervention with the thrombus removal and major venous resection. The major vessel involvement complicates surgery. It is much more difficult to achieve negative resection margins. The risk of damage to the main vessels during tumor mobilization increases and, as a result, the risk of hemorrhagic complications increases as well. An interdisciplinary approach reduces the risk of surgical complications and helps achieve radical tumor resection. Our purpose was to analyze the rates of tumor thrombosis in malignant tumors of bones and soft tissues and evaluate the results of surgical treatment. Methods: 115 patients (mean age 46 years) with malignant tumors of bones and soft tissues received surgical treatment in 2020-2021. The most common histological subtypes were synovial sarcoma (25.3%), pleomorphic sarcoma (18.2%), and liposarcoma (15.6%). Venous thrombosis of the lower extremity veins was diagnosed at the stage of preoperative preparation in 17 patients (14.8%), the femoral segment was more often affected (70.6%). All patients received anticoagulant therapy. The tumor genesis of a thrombus was confirmed intraoperatively in 7 patients. Thus, the incidence of tumor thrombosis in malignant tumors of bones and soft tissues was 6%. All patients underwent tumor removal, thrombectomy, and the femoral or iliac venous segment resection. Results: The following complications were observed in the postoperative period: seroma - 5 cases (29.4%), lymphorrhea - 12 (70.5%), swelling of the lower limb - 12 cases (70.5%). Conclusions: Tumor thrombosis in malignant tumors of bones and soft tissues of the lower extremities is not a rare complication, it requires timely diagnosis and an expanded intervention to achieve negative resection margins and reduce the risk of embolism.
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers.
Authors: Emilie Wong Chong, France-Hélène Joncas, Nabil Georges Seidah, Frédéric Calon, Caroline Diorio, Anne Gangloff
Journal: Journal of Clinical Oncology (2022)

e12547 Background: Cholesterol plays an important role in sustaining tumor growth and metastasis in a large variety of cancers. New and powerful cholesterol-lowering drugs are being used in combination to treat cardiovascular diseases. As drugs directed against PCSK9 (evolocumab, alirocumab, inclisiran), ANGPTL3 (evinacumab) and Lp(a) (pelacarsen) are available, it becomes of interest to assess the circulating levels of these drug targets and their role in cancers. Our purpose here is to compare circulating levels of PCSK9, ANGPTL3, and Lp(a) in women with stage III breast cancer versus women with a premalignant or benign breast lesion. Methods: Twenty-three plasma samples from women diagnosed with a stage III breast cancer (ductal, lobular or mixed) were matched for age with twenty-three plasma samples from women bearing premalignant (stage 0, n=9) or benign (n= 14) breast lesions. Lipid profile (Apo B, total cholesterol, HDL and triglyceride levels) and Lp(a) were measured on a Roche Modular analytical platform. LDL levels were calculated with the Friedewald formula. ANGPTL3 and PCSK9 plasma levels were quantitated by ELISA. Difference between breast disease groups was deemed significant when group-comparison generated p-values &lt; 0.05. Results: PCSK9 levels were significantly higher in women with stage III breast cancer compared to age-matched counterparts presenting a benign lesion (95.9 +/- 27.1 ng/mL vs. 78.5 +/- 19.3 ng/mL, p&lt;0.05, n=14). Moreover, PCKS9 levels positively correlated with breast disease severity (benign, stage 0, stage III) (Rho=0.34, p&lt;0.05, n=46). In contrast, ANGPTL3, Lp(a) or lipid plasma levels did not display any correlation with breast disease severity. Conclusions: In this cohort of 46 women, PCSK9 levels increased along with the severity of breast disease. Given that PCSK9 plays an important role in maintaining cholesterolemia and has been shown to degrade MHC-I on tumor cells, impeding immune T-cells response to tumors, confirmation of PCSK9 elevation in a larger cohort would pave the way for trials studying lipid-lowering drugs as adjuvant treatments in breast cancer.
Evaluation of an automated artificial intelligence (AI)/ natural language processing (NLP) engine to match patients (pts) with advanced solid cancers to biomarker-driven early phase (EP) clinical trials.
Authors: Cienne Morton, Daniel Ruta, Chara Stavraka, Kaiser Anam, James F. Spicer, Aoife Regan, Siru Sengul, George Cernile, Yulia Borecki, Taralyn Schwering, Harpreet Rai, Phil Brierley, Oenone Duroe, Alan Quarterman, Debashis Sarker
Journal: Journal of Clinical Oncology (2022)

e13513 Background: The increasing complexity of precision medicine in oncology creates significant challenges in identification of pts for biomarker-driven clinical trials. Worldwide expansion of genomic testing will identify more pts with potentially actionable alterations, but the manual task of matching pts to clinical trials requires laborious interpretation of fragmented medical information and knowledge of suitable trial eligibility criteria. Inspirata’s Trial Navigator (TN) solution uses AI and NLP to automatically extract relevant information from both patient medical records and trial protocols to identify appropriate trials. We conducted a retrospective study to evaluate the ability of TN to match pts referred to the Guy’s Hospital EP trials unit. Methods: Anonymised referral letters and genomic reports for pts referred from Jan 2019 to Dec 2020 were used. A subset was used to train TN to extract relevant variables for matching against eligibility criteria for all UK Experimental Cancer Medicine Centre (ECMC) Network trials open within 160 km of Guy’s Hospital at the time of referral, favouring biomarker-matched studies. Finally, TN was tasked with finding 5 ECMC trial matches for 40 referred pts. Matches were scored for eligibility and tumour and/ or biomarker suitability using a quality index (QI): 0, ineligible; 1, generic match; 2, tumour match; 3, biomarker match; 4, tumour and biomarker match. Results: Of 40 pts, most common tumour groups included gastrointestinal (55%), HNSCC (20%) and gynae (10%). TN was able to correctly identify at least 1 suitable trial (median = 4) for 39/40 pts (97%). Selection biomarkers were available for 27 pts, of whom 21 (78%) were matched to at least one appropriate biomarker-directed trial, 5 (12%) were matched to biomarker-agnostic trials and one was not correctly matched due to exclusion for progressive CNS metastases. Of 13 pts without biomarker information, 11 (84%) were matched to at least 1 tumour-appropriate trial and 2 to tumour-agnostic trials. Of all 200 trial matches, 134 (67%) were appropriately matched, of which 80 (59%) were external to Guy’s Cancer centre. Conclusions: TN successfully matched 90% of these preselected cancer pts to an appropriate biomarker- or tumour-directed trial, indicating potential to improve access and recruitment to early phase cancer trials, including those external to the primary treating site with which referrers may not be familiar. A prospective multicentre evaluation of TN is warranted to further define improvements in trial recruitment and efficiency.[Table: see text]